The opiate mu receptor site will be mapped using high-resolution x-ray measurements of the electron density distribution (EDD) and molecular electrostatic potential (MEP) of opiates and related molecules. These properties, until recently, could only be obtained from theoretical calculations. With the recent development of experimental x-ray methods, it is now possible to obtain from the same experiment not only the shape of the drug molecule, but also the EDD and MEP, which along with geometry, dictate the strength of a drug-receptor interaction. Studies of other biological model compounds show that these electronic factors are now measurable with an accuracy at least equivalent to the best calculations on small molecules. Initially, a series of rigid opiates (morphine, oxymorphine, nalorphine, and naloxone) will be studied which span the range from potent agonist to pure antogonist. These studies will be used to identify both the stereochemical and electronic requirements of the receptor site, and to attempt to understand how such small structural modifications may result in radical differences in analgesic activity. A model for the receptor will be constructed at atomic resolution by assuming that it will be complementary both in shape and electronic character to the drug molecule. Charged species and molecular fragments will be positioned to yield interaction energies which follow drug binding and activity. Once the receptor site has been adequately characterized, studies will be made of progressively more flexible drugs with opiate-like activity. This data will be used to define the similarities in both the structural and electronic character of the active drugs, and to further characterize the receptor site The long-term objective is to develop the x-ray measurement of EDD's and MEP's into a tool of general use for the study of drug-receptor and protein-ligand interactions.